title: Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.
abstract: Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [4].
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Beer
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.forename: Vineeta
authors.initials: V
authors.lastname: Agarwala
authors.forename: Janne
authors.initials: J
authors.lastname: Molnes
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: Herman
authors.initials: H
authors.lastname: Taylor
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Henrik
authors.initials: H
authors.lastname: Irgens
authors.forename: Ervin
authors.initials: E
authors.lastname: Fox
authors.forename: Frank
authors.initials: F
authors.lastname: Burslem
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Jeff K
authors.initials: JK
authors.lastname: Trimmer
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Pål R
authors.identifier: 0000000303046728
authors.initials: PR
authors.lastname: Njølstad
authors.forename: Tim
authors.initials: T
authors.lastname: Rolph
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: David R
authors.initials: DR
authors.lastname: Cox
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D000328:Adult; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012306:Risk; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000081410:Germinal Center Kinases; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C093970:NEUROD1 protein, human; C084010:pancreatic and duodenal homeobox 1 protein